Myocardial angiogenesis has been considered a therapeutic target for improving cardiac function by increasing perfusion, but clinical trials to deliver VEGF-A or FGF have not been successful and resulted in aberrant and leaky vessels. Considering that formation of vessels normally requires the concerted actions of multiple factors, we searched for mechanisms of coordinate transcriptional control of angiogenic factor genes. We present data that the transcription factor RBPJ regulates nearly all angiogenic genes examined in vivo. Cardiomyocyte-specific deletion of RBPJ [J Recombination signal sequence Binding Protein, aka CSL-1 and Suppressor of Hairless, Su(H)] in the adult mouse heart reveals that RBPJ represses angiogenic factor genes in the normal heart. Ischemic injury releases RBPJ-repression to stimulate an increase in microvessel density in the ventricular wall. Remarkably, genetic attenuation of RBPJ in cardiomyocytes preserves heart function and survival post-MI, possibly reflecting increased vessel density and/or direct protective effects of genes induced by the loss of RBPJ. The goal of this project is to define the mechanism(s) by which RBPJ promotes angiogenesis and myocardial protection after MI, and evaluate whether modulating RBPJ and/or its interacting proteins would therapeutically enhance these processes after ischemic or other injury. Aims 1 and 2 evaluate the regulation of angiogenesis by defining the transcriptional basis for the coordinated control of angiogenic factor genes in normal and ischemic hearts (Aim 1) and verifying the functionality of the new vessels (Aim 2). Aims 3 and 4 expand the project beyond angiogenesis to follow up additional preliminary data suggesting that inhibition RBPJ stimulates protective signal transduction pathways and changes in energy substrate utilization that might contribute to myocardial cell survival post-MI. In summary, this project will study a new paradigm for the control of myocardial angiogenesis and evaluate RBPJ and its interacting partners as candidate therapeutic targets for the treatment of ischemic heart disease.